Natural and synthetic retinoids offer exciting possibilities as epithelial cancer-preventing and cancer-treatment agents. Although their antineoplastic potency has been demonstrated in numerous animal models, their usefulness in human malignancy is only now being ascertained. Furthermore, the mechanism(s) whereby retinoids influence epithelial differentiation remains unknown. In this proposal we will be assessing the subcellular basis for the retinoids' activity against cancer, focusing on changes in membrane structures, particularly gap junctions, in microfilaments, and in the basement membrane in human basal cell carcinomas treated with topical retinoids. In addition, we wish to ascertain by clinical testing if the retinoids are clinically useful for the therapy of established basal cell cancers. Preliminary results indicate that retinoids stimulate a proliferation in the size and number of gap junctions in basal cell cancer cell membranes. Since gap junctions are important for intercellular communication and cell regulation, this may represent one possible mechanism for the retinoid's antineoplastic activity.